U.S. patent number 4,724,266 [Application Number 07/076,240] was granted by the patent office on 1988-02-09 for pharmaceutical composition with antithrombotic activity.
This patent grant is currently assigned to Godecke Aktiengesellschaft. Invention is credited to Hartmut Osswald, Gerhard Satzinger, Ute Weiershausen, Gunter Wolf.
United States Patent |
4,724,266 |
Satzinger , et al. |
February 9, 1988 |
Pharmaceutical composition with antithrombotic activity
Abstract
The present invention provides combination of materials for
strengthening the antithrombotic action of acetylsalicylic acid. It
covers a composition which contains diltiazem or a pharmaceutically
acceptable acid-addition salt thereof in combination with
acetylsalicylic acid. It also forms the new compound diltiazem
acetysalicylate. It also covers compositions containing the above
and methods for using the compositions or compound.
Inventors: |
Satzinger; Gerhard (Denzlingen,
DE), Wolf; Gunter (Freiburg, DE), Osswald;
Hartmut (Waldkirch, DE), Weiershausen; Ute
(Gundelfingen, DE) |
Assignee: |
Godecke Aktiengesellschaft
(Berlin, DE)
|
Family
ID: |
6306505 |
Appl.
No.: |
07/076,240 |
Filed: |
July 21, 1987 |
Foreign Application Priority Data
|
|
|
|
|
Jul 31, 1986 [DE] |
|
|
3626097 |
|
Current U.S.
Class: |
560/143;
540/488 |
Current CPC
Class: |
A61K
31/60 (20130101); A61K 31/60 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
31/60 (20060101); A61K 31/55 (20060101); C07C
69/00 (20060101); C07C 69/157 (20060101); C07D
281/10 (20060101); C07D 281/00 (20060101); C07C
069/00 () |
Field of
Search: |
;560/143 ;540/488 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Killos; Paul J.
Attorney, Agent or Firm: Anderson; Elizabeth M.
Claims
We claim:
1. A compound having the name dilatiazem acetylsalicylate.
2. A pharmaceutical composition comprising from > 60 to 180 mg
diltiazem or a pharmaceutically acceptable acid addition salt
thereof with from about 10 to 300 mg acetylsalicylic acid.
3. A thrombolitically-effective pharmaceutical composition
comprising an effective amount of a compound according to claim 1
or a composition according to claim 2 together with a
pharmaceutically acceptable carrier.
4. A method of treating or preventing thromboembolic diseases in
mammals which comprises administering to said mammal a
pharmaceutical composition according to claim 3 in unit dosage
form.
Description
BACKGROUND OF THE INVENTION
The antithrombotic action of the acetylsalicylic acid is known
(Med. Klin., 76, 692/1981) but the optimum dosage is still open to
debate. Recommendations vary between 300 mg/day and 3.times.500
mg/day or 4.times.325 mg/day. Acetylsalicylic acid brings about an
irreversible inhibition of cyclooxygenase, an enzyme which produces
thromboxane A.sub.2 (TXA.sub.2) in the thrombocytes. Without
TXA.sub.2, no arrest of hemorrhage, as desired effect, takes place
and no aggregation of the blood platelets which is necessary for
thrombogenesis. At the same time, however, acetylsalicylic acid
also inhibits the cyclooxygenase of the intima of the blood vessels
so that the endogenic aggregation inhibitor epoprostenol,
PGI.sub.2, cannot be formed. In this way, acetylsalicylic acid
obtains a thrombogenic potency. Since the cyclooxygenase of the
thrombocytes is more sensitive towards acetylsalicylic acid and is
more slowly regenerated as that of the inner blood vessel walls, it
is assumed that a certain differentiation of the acetylsalicylic
acid effect can be achieved via the dosage.
On the one hand, because of the reduction of the acetylsalicylic
acid side effects, which can be considerable and manifest
themselves, especially in the gastrointestinal tract and in the
kidneys, and, on the other hand, for the above-mentioned reasons,
it is of decisive therapeutic importance to keep the dosage of the
acetylsalicyclic acid as low as possible. For the purposes of the
present invention, this is achieved by a combination of
acetylsalicylic acid with diltiazem.
SUMMARY OF THE INVENTION
The present invention is concerned with a combination of two
effective substances which exhibit synergistic action; thereby
strengthening the antithrombotic action of acetylsalicylic
acid.
A rational prophylaxis and therapy must be oriented to the
pathogenesis of the disease in question. In the case of diseases of
the blood vessels involving occlusion, the thrombocytes are of
decisive importance. This applies to the initial thrombogenesis in
the arterial system as well as to the formation of coagulation
thrombi in the venous circulation. Recent experimental knowledge
also indicates that arteriopathies in the widest sense are to be
regarded as being the result of a disturbed relationship between
the walls of the blood vessels, that is the endothelium, and the
thrombocytes. This knowledge provides new assumptions for
appropriate causal therapeutic measures.
Since the in vivo thrombocyte aggregation is, in all probability,
the result of simultaneous activation or production of several
aggregationic factors, such as platelet-activating factor (PAF),
adrenaline, ADP/ATP and lipoxygenase and cyclooxygenase products of
arachidonic acid an extensive therapeutic effect cannot be expected
from the action of a cyclooxygenase inhibitor, such as
acetylsalicyclic acid or sulfinpyrazone, alone.
Consequently, it is an object of the present invention to provide a
new composition for the therapy and prophylaxis of thromboembolic
diseases.
One aspect of the present invention is a new compound, diltiazem
acetylsalicylate. Another aspect is a new pharmaceutical
composition comprising from more than 60 to about 180 mg of
diltiazem or a pharmaceutically acceptable acid addition salt
thereof with from about 10 to 300 mg acetylsalicylic acid.
Still another aspect is a thrombolitically-effective pharmaceutical
composition comprising an effective amount of the above composition
together with a pharmaceutically acceptable carrier.
Yet another aspect is a method of treating or preventing
thromboembolic diseases in mammals which comprises administering to
said mammal the above pharmaceutical composition in unit dosage
form.
DETAILED DESCRIPTION
Thus, according to the present invention, there is provided a
synergistic combination of materials for strengthening the
antithrombic action of acetylsalicyclic acid, wherein it contains
diltiazem or a pharmaceutically acceptable acid-addition salt
thereof in combination with acetylsalicylic acid.
Thromboembolic diseases are understood to include such diseases as:
peripheral arterial and venous occlusive diseases/arteriopathies,
prevention of thromboembolic complications; coronary heart disease,
prophylaxis after heart infarct prevention of venous thromboses and
arterial embolisms; cerebrovascular blood vessel diseases,
ischaemias, insultus as a result of thromboembolic incidents;
arteriosclerosis, reduction of risk factors; migraine, prophylaxis
and therapy; and Raynaud syndrome, prophylaxis and therapy in the
case of thromboembolic disposition.
It is surprising that diltiazem, a known coronary vasodilatory,
even in combination with extraordinarily low dosages of
acetylsalicylic acid, strengthens its therapeutic, thrombocyte
aggregation-inhibiting action in a synergistic manner. A weakly
inherent action of diltiazem inhibiting the aggregation of the
blood platelets would be explicable since the activation of the
phospholipase A.sub.2 of the thrombocytes, the activation of the
actomyosin of the platelets, and possibly also the platelet-derived
growth factors (PDG) on the intima are under the control of calcium
ions. However, it was not to have been foreseen that the
combination of subtherapeutic dosages of diltiazem and
acetylsalicylic acid would exercise a strong antiaggregating
effect. Thus, because of the increased safety and effectiveness,
the combination according to the present invention represents a
real therapeutic advance.
A preferred dosage unit comprises 60 to 180 mg diltiazem or an acid
addition salt thereof in combination with 10 to 300 mg
acetylsalicylic acid and possibly also conventional adjuvants and
carrier materials.
A more preferred dosage unit comprises 80 to 100 mg diltiazem or an
acid addition salt thereof in combination with 50 to 100 mg of
acetylsalicylic acid and possibly also conventional adjuvants and
carrier materials.
As salts of diltiazem, there can be used the usual ones with
organic and inorganic acids. The salts are usually obtained by
neutralizing the base with appropriate inorganic or organic acids.
As acids, there can be used, for example, hydrochloric acid,
sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid,
tartaric acid, lactic acid, citric acid, malic acid, salicylic
acid, ascorbic acid, malonic acid, and succinic acid.
Since diltiazem is basic by nature, the acetylsalicylic acid can
also act directly as a salt former, especially because this salt
contains the active materials in a very good relationship.
One-hundred thirty mg of the new diltiazem acetylsalicylate contain
about 90 mg of diltiazem active material and 40 mg of
acetylsalicylic acid active material. A dosage unit of 65 mg of
this salt contains about 45 mg diltiazem and 20 mg of
acetylsalicylic acid. Thus, a composition with 100 mg diltiazem
acetylsalicylate contains, per dosage unit, 30,3 mg acetylsalicylic
acid and 69.7 mg diltiazem, which corresponds to a weight ratio of
1:2.3.
Diltiazem, or an acid-addition salt thereof, and acetylsalicylic
acid, as well as diltiazem acetylsalicylate, can be employed in
conventional compositions and in admixture with conventional
pharmaceutically acceptable carriers and diluents.
The compositions according to the present invention can be
administered orally or parenterally in liquid or solid form. As
injection solution, water is preferably used which contains the
additives usual in the case of injection solutions, such as
stabilizing agents, solubilizing agents, or buffers.
The compositions can be present as conventional galenical
formulations, such as tablets or capsules.
Additives of this kind include, for example, tartrate and citrate
buffers; ethanol; complex formers, such as
ethylenediamine-tetraacetic acid and the nontoxic salts thereof, as
well as high molecular weight polymers, such as liquid polyethylene
oxide, for viscosity regulation. Solid carrier materials include,
for example, starch; lactose; mannitol; methyl cellulose; talc;
highly dispersed silicic acid; high molecular weight fatty acids,
such as stearic acid; gelatine; agar-agar; calciumphosphate;
magnesium stearate; animal and vegetable fats; and solid high
molecular weight polymers, such as polyethylene glycol.
Compositions suitable for oral administration can, if desired,
contain additional flavoring and/or sweetening agents.
The individual dosages of the new compositions are in the range of
from 50 to 400 mg in the case of enteral administration and from
about 5 to 50 mg in the case of parenteral administration.
Because of the known stability problems with solutions of
acetylsalicylic acid, as parenteral preparations lyophilisates are
especially preferred, which are first brought into solution shortly
before use.
The present invention is explained in more detail on the basis of
the following comparative experiments.
COLLAGEN-INDUCED THROMBOCYTE AGGREGATION MATERIALS AND METHODS
The experimental animals used were male Sprague-Dawley SIV 50 rats
with a body weight of 200 g. The test substances were dissolved in
water and administered to the animals twice daily by means of a
stomach tube. The first administration took place at 3:00 PM on the
preceding day and the second administration at 8:00 AM of the
experimental day. After the first administration, food was removed
from the animals but they still received water. Per administration,
the animals received, in a volume of 1 ml/200 g body weight, the
following dosages:
______________________________________ placebo only water 1st
dosage 30 mg diltiazem/kg 2nd dosage 100 mg diltiazem/kg 3rd dosage
5 mg acetylsalicylic acid/kg 4th dosage 30 mg diltiazem/kg and 5 mg
acetylsalicylic acid/kg ______________________________________
At 9:00 AM on the experimental day, i.e., one hour after the second
administration, blood was taken from the retroorbital venous plexus
of the animals under ether narcosis. Nine parts of blood were mixed
with one part of 3.8% (w/v) trisodium citrate solution. After
lowspeed centrifuging of the mixture at ambient temperature, the
platelet-rich plasma (PRP), corresponding to the erythrocyte-free
supernatant, was removed and adjusted to a standard concentration
of 400,000 .mu.l. The aggregation test was carried out according to
the method of Born (Nature, 194, 927-929/1962). The measurement
instrument used was a universal aggregometer (Braun, Melsungen)
connected with an Eppendorf photometer 1100M (Netheler & Hinz,
Hamburg).
In the experiment, in each case 800 .mu.l PRP were equilibrated in
the aggregometer for three minutes at 37.degree. C. and then, by
the addition of 35 .mu.l collagen suspension (collagen reagent
HORM, Hormon Chemi, Munchen), the aggregation was initiated. A
compensation recorder registered the change of transmission in the
following five minutes. With increasing aggregation, in this test
the transmission increases and the extinction decreases. The
changes registered five minutes after addition of the collagen were
evaluated and are set out in the following Table 1. The values are
given as percentages, the extinction difference between PRP and
platelet-free plasma serving as 100% value. The aggregation values
obtained are set out in Table 1 below.
TABLE 1 ______________________________________ Test Composition
Aggregation -x .+-. S.D. ______________________________________
Placebo 65 .+-. 12 1 30 mg/kg diltiazem 63 .+-. 10 2 100 mg/kg
diltiazem 58 .+-. 10 3 5 mg/kg acetylsalicylic acid 37 .+-. 12 4 30
mg/kg diltiazem and 19 .+-. 15 5 mg/kg acetylsalicylic acid
______________________________________ -x .+-. S.D. in each case
from six individual experiments.
From the above Table 1, it can be seen that dosage 4 results in a
surprisingly low aggregation value.
EXAMPLE
Diltiazem-acetylsalicylate
A solution of 731,4 mg (1,76 m mol) diltiazem and 317,9 mg (1,76 m
mol) acetylsalicylic acid is prepared in 10 ml water. The solution
obtained is evaporated to dryness. The amorphous colourless residue
is pulverized to a white powder.
Yield: 1000 mg.
The salt exhibits in the NMR-spectrum (solution in CDCl.sub.3) the
typical chemical shift expected for a salt, which is demonstrated
in the following Table II:
TABLE II ______________________________________ Coordination and
comparison of the NMR-signals of the diltiazem - acetylsalicylate -
salt. Chemical Shift .delta. in ppm Multi- Fragment BASE SALT
.vertline..DELTA..delta..vertline. plicity
______________________________________ ##STR1## 1,90 1,90 -- S
N(CH.sub.3).sub.2 2,27 2,60 0,33 S NCH.sub.2 2,46 2,94 0,48 M 2,69
3,15 0,46 M OCH.sub.3 3,82 3,82 -- S NCH.sub.2 3,71 4,08 0,37 M
4,42 4,46 0,04 M CH 5,01 5,01 -- D CH 5,16 5,13 0,03 D p-Methoxy-
aromatic res. m. CH 6,89 6,90 0,01 D o. CH 7,44 7.39 0,05 D Basic
aromat. 7,26 7,25 0.01 M H residue 7,48 7,5 , M 7,48 7,5 , M 7,69
7,68 0,01 DM Acetylsali- cylic acid ##STR2## 2,25 S arom. CH 7.04
DD 7,25 M 7,5 M 7,96 DD ______________________________________
* * * * *